Introduction and Objective: Adipose tissue (AT) is a central regulator of energy homeostasis and systemic metabolism. Dysfunctional AT expansion during obesity is a major driver of metabolic diseases, particularly type 2 diabetes. Mesenchymal progenitor cells (MPCs), a heterogeneous and dynamic cell population, play a critical yet poorly understood role in AT expansion and function. In this study, we aim to understand the precise cell type changes in AT during the development of obesity.Methods: We used single-cell RNA sequencing of visceral AT to identify distinct subpopulations of cells that emerge in obesity. We identified factors enriched in these subpopulations and used knockout and overexpression techniques both in vivo and in vitro to determine their function in AT homeostasis.Results: We identified a distinct MPC subpopulation that emerges in obesity and shares a core gene signature with cancer-associated fibroblasts (CAFs). These cells exhibit high expression of the transcription factor Sox4. After deleting or overexpressing Sox4 in MPCs using both in vivo and in vitro systems, we found that Sox4 overexpression in MPCs decreases adipocyte differentiation, worsens glucose metabolism, and promotes AT fibrosis and inflammation. Conversely, deletion restores AT homeostasis in obesity models. Additionally, CAF-like cells contribute to AT dysfunction through the secretion of various factors including Midkine, a growth hormone and cytokine. Inhibition of Midkine reduced inflammation and improved glucose homeostasis without affecting body weight.Conclusion: Our findings reveal Sox4 as a key regulator of CAF-like cells in AT and highlight Midkine’s role in metabolic dysfunction. Targeting these pathways could help prevent obesity-related diseases.
K. Drareni: None. R.P. Calhoun: None. L. Cheng: None. S.E. Traynor: None. D. Merrick: None. P. Seale: Advisory Panel; iTeos. Consultant; Merck & Co., Inc.
American Diabetes Association (1-23-PDF-130); NIH
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